Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2 like 2 ((Keap1-Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive effects of various inducers and small molecule Nrf2 activators, such as sulforaphane (SFN), curcumin, and chalcone derivatives have been identified as cancer chemopreventive agents.
[6]-shogaol (6S), a major component of dry ginger, was previously identified as an activator of Nrf2 in colon epithelial cells. With an α,β-unsaturated carbonyl group in the alkyl tail, 6S is a typical Michael acceptor and can activate Nrf2 via alkylation of cysteine residues of Keap1 protein. Alkylation of one or more of the cysteine residues of Keap1 by xenobiotic electrophiles appears to be one signaling mechanism for the regulation of antioxidant response element (ARE) activity through Nrf2.
However, there is an ongoing need for the identification of additional and potentially more active Nrf2 activators. There is also a need for additional compounds that could be used to treat diseases and conditions associated with oxidative stress and/or inflammation and/or that could be treated by the activation of Nrf2. Such diseases include both chronic and acute conditions, such as, for example, atherosclerosis, diabetes-related disease, and autoimmune diseases, among others.